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AMPA receptor trafficking regulates social behaviors in autism

AMPA 受体贩运调节自闭症的社会行为

基本信息

批准号：
9447811
负责人：
Richard L Huganir
金额：
$ 40.89万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-18 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9447811
关键词：
AMPA Receptors Address Affect Animals Autistic Disorder Behavioral Binding Biological Assay Biotin Brain C-terminal Candidate Disease Gene Clinical Complex Congenic Strain Defect Development Electrophysiology (science)Equilibrium Event Exhibits Functional Magnetic Resonance Imaging GRIP1 gene Genes Glutamates Grant Human Kinetics Knock-in Mouse Knockout Mice Label Medial Mediating Methods Microscopy Modeling Molecular Mus Mutant Strains Mice Mutation Neurons Neurosciences Opsin Pathogenesis Pathway interactions Patients Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Prefrontal Cortex Proteomics Recycling Regulation Role Scaffolding Protein Signal Transduction Signaling Protein Social Behavior Social Interaction Surface Synapses Synaptic Transmission Testing Tissues Two-Hybrid System Techniques Update Validation Work Yeasts autism spectrum disorder density effective therapy endophenotype gain of function gain of function mutation glutamatergic signaling grasp hippocampal pyramidal neuron in vivo insight loss of function mouse model neural circuit neuromechanism neurotransmission new therapeutic target novel optogenetics protein transport social tool trafficking two-photon

项目摘要

Abstract Autism spectrum disorders are clinically and genetically heterogeneous. Identification of convergent molecular pathways and neural circuits underlying autism endophenotypes are crucial to discovery of novel drug targets for development of effective therapies. Glutamate mediates the majority of excitatory neurotransmission in the CNS. Glutamate receptor interacting proteins 1/2 (GRIP1/2) are neuron-enriched scaffolding proteins with 7 PDZ domains. PDZ domains 4-6 of GRIP1/2 bind the c-terminal domain of AMPA receptor 2/3 (GluA2/3). Loss of Grip1/2 expression in mice results in delayed recycling of GluA2 in neurons and increased sociability and social interactions. Studies of AMPA-signaling proteins identified an enhanced GluA2-S880 phosphorylation in prefrontal cortex in the mutant mice. In a screen of glutamate signaling genes in patients with autism, we found gain-of-function mutations in GRIP1-PDZ4-6 that contribute to reduced social interactions in autism patients. To study mechanisms of GluA2 trafficking in modulating social behaviors, we generated knock-in mice carrying a human autism-associated mutation I586L. Grip1-I586L mice show increased binding with GluA2 in brain lysates and exhibit a reduced sociability in the modified three-chamber sociability tests. We hypothesize that Grip1-I586L alter GluA2 recycling and surface expression resulting in increased AMPA synaptic strength and enhanced local connectivity in prefrontal cortex. We will study molecular mechanisms responsible for GluA2 trafficking defects in Grip1-KO and Grip1-I586L mice. We will investigate neural mechanisms of disturbance of AMPA signaling in prefrontal cortex causing social behavioral deficits in autism using electrophysiology and optogenetic methods. The results shall provide valuable insights into neural mechanisms of AMPA signaling defects in social behavioral deficits in autism.

摘要